CN1697836A

CN1697836A - Substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid compounds as NMDA-antagonists

Info

Publication number: CN1697836A
Application number: CNA028195124A
Authority: CN
Inventors: M·格拉奇; M·普泽沃斯伊; W·G·恩格伯格; E·雷斯米勒; P·布洛姆斯-芬克; C·莫尔; U·-P·贾古斯奇
Original assignee: Gruenenthal GmbH
Current assignee: Gruenenthal GmbH
Priority date: 2001-08-03
Filing date: 2002-08-05
Publication date: 2005-11-16
Also published as: ATE402178T1; RU2004106533A; CO5550438A2; EP1412361A1; HUP0400800A3; NZ531372A; MXPA04000953A; WO2003014124A1; DE50212538D1; NO20040471L; IL160160A0; CA2456124A1; KR20040020078A; BR0211734A; EP1412361B1; ECSP044968A; ZA200401725B; US20040248889A1; US7199130B2; HUP0400800A2

Abstract

The invention relates to substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid derivatives, to methods for the production thereof, medicaments containing these compounds, and to their use for producing medicaments for certain indications, particularly for treating pain.

Description

As 5,6 of the replacement of nmda antagonist, 6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-carboxylic acid derivative

Technical field

The present invention relates to replace 5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-carboxylic acid derivative, its preparation method contains the pharmaceutical preparation of these compounds, and these compounds are used for specific adaptations disease in preparation, especially for the application in the pharmaceutical preparation of treatment pain.

Background technology

In medical treatment, treatment chronic and non-chronic pain is extremely important.Need effective methods of treatment to provide the chronic and non-chronic pain treatment of specific aim and target in worldwide, this is meant the effective and gratifying pain therapy of position from the patient.From a large amount of science articles that relate to application pain killer or the research of basic nociception of nearest publication, can be clear that this point.

Opioid commonly used for example morphine serious effective to extremely serious treatment of pain camber.Yet, known side effects limit their application, these side effects for example have respiration inhibition, vomiting, sedative effect, constipation and resistance development.In addition, for neuropathic pain or the tumour patient accidental pain that can stand especially wherein, their validity is relatively poor.

Opioid is to realize its analgesic effect by combining with the membrane receptor that belongs to G-protein linked receptor family.By determining the biochemistry and the pharmacology feature of these receptor subtypes, people expect that the hypospecificity opioid can have and are different from for example effect/side effect profile of morphine.Now, further pharmacological research has temporarily disclosed these Opioid Receptors and has had a plurality of hypotype (μ ₁, μ ₂, κ ₁, κ ₂, κ ₃, δ ₁And δ ₂).There are other acceptor and ionic channel in the system of pain management generation and transmission, to play the essence effect.The NMDA ionic channel plays particularly important, carries out via this passage because there is a high proportion of cynapse to exchange.This passage is controlled at the calcium ion-exchanged between neuronal cell and its environment.

The development of patch clamp technology makes it possible to illustrate the important biological value of ionic channel selective substances.Therefore, can clearly confirm the influence of calcium ion in the nmda antagonist pair cell.Also establishedly be that these materials self have its oneself anti-nociception ability (for example ketamine).An important fact is, its mode of action is significantly different with for example opioid, because nmda antagonist is the calcium balance that directly acts on cell, transmission has decisive role and the calcium balance of cell is for pain.Therefore, this is can successfully treat neuropathy type pain for the first time.

Article J.Med.Chem. (1992) 35,1954-1968, J.Med.Chem. (1992) 35,1942-1953 and Med.Chem.Res. (1991) 1; Having described among 64-73 and patent application EP386 839, WO 97/12879 A1, WO 98/07704 A1 and WO 98/42673 A1 is the multiple nmda antagonist of tetrahydroquinoline derivative.At these publications, especially mentioned multiple possible indication in the patent application, particularly including pain therapy.Yet the effectiveness of these materials and operability are still unclear so far, so still need other material.

Summary of the invention

An object of the present invention is to provide and be suitable for treating pain, particularly including chronic and analgesic activity material, especially nmda antagonist neuropathic pain.These materials should also show the least possible side effect, for example feel sick, vomiting, dependence, respiration inhibition or constipation.Therefore, the invention provides 5,6 shown in the general formula I, 6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-carboxylic acid derivative

Described compound is the form of its preparation, or the form of its acid or alkali, or the form of its salt, particularly physiological acceptable salt, or the form of its solvate, particularly hydrate; The form of its physiological acceptable salt that forms with positively charged ion or alkali or with negatively charged ion or acid particularly; Can choose wantonly and be its racemic modification form, the steric isomer that it is pure, particularly enantiomorph or diastereomer form, or steric isomer, particularly enantiomorph or diastereomer are with the form of mixtures of any required mixed ratio;

Wherein

R ¹, R ², R ³And R ⁴Be independently from each other

H, F, Cl, Br, I, CN, NO ₂C ₁-C ₁₈-alkyl, C ₂-C ₁₈-alkenyl or C ₂-C ₁₈-alkynyl, described group are respectively side chains or unbranched, and single replacement is polysubstituted or unsubstituted; C ₃-C ₈-cycloalkyl, described group are saturated or undersaturated, single replace polysubstituted or unsubstituted, or wherein at least one ring carbon atom by N, S or the corresponding heterocycle of O alternate; Alkylaryl or miscellaneous alkyl aryl, described group are respectively that single replacement is polysubstituted or unsubstituted; Aryl or heteroaryl, described group are respectively that single replacement is polysubstituted or unsubstituted;

OR ¹¹, OC (O) R ¹¹, C (O) R ¹¹, C (O) OR ¹¹, C (O) NR ¹¹R ^{11 '}, NR ¹¹R ^{11 '}, S (O ₂) R ¹¹Or SR ¹¹, R wherein ¹¹And R ^{11 '}Be independently from each other

H; C ₁-C ₁₈-alkyl, C ₂-C ₁₈-alkenyl or C ₂-C ₁₈-alkynyl, described group are respectively side chains or unbranched, and single replacement is polysubstituted or unsubstituted; C ₃-C ₈-cycloalkyl, described group are saturated or undersaturated, single replace polysubstituted or unsubstituted, or wherein at least one ring carbon atom by N, S or the corresponding heterocycle of O alternate; Alkylaryl or miscellaneous alkyl aryl, described group are respectively that single replacement is polysubstituted or unsubstituted; Aryl or heteroaryl, described group are respectively that single replacement is polysubstituted or unsubstituted;

R ⁵Be selected from

R ⁶Be selected from

R ¹²Or ZR ¹², Z=C wherein ₁-C ₆-alkyl, C ₂-C ₆-alkenyl or C ₂-C ₆-alkynyl, described group are respectively side chains or unbranched, and single replacement is polysubstituted or unsubstituted, wherein R ¹²Be selected from

H; C ₁-C ₁₂-alkyl, C ₂-C ₁₂-alkenyl or C ₂-C ₁₂-alkynyl, described group are respectively side chains or unbranched, and single replacement is polysubstituted or unsubstituted; C ₃-C ₈-cycloalkyl, described group are saturated or undersaturated, single replace polysubstituted or unsubstituted, or wherein at least one ring carbon atom by S, O or the corresponding heterocycle of N alternate; Aryl or heteroaryl, described group are respectively that single replacement is polysubstituted or unsubstituted;

C (O) R ¹³, C (O) OR ¹³, C (S) R ¹³, C (S) OR ¹³Or S (O ₂) R ¹³, R wherein ¹³Be selected from

H; C ₁-C ₁₀-alkyl, C ₂-C ₁₀-alkenyl or C ₂-C ₁₀-alkynyl, described group are respectively side chains or unbranched, and single replacement is polysubstituted or unsubstituted; C ₃-C ₈-cycloalkyl, described group are saturated or undersaturated, single replace polysubstituted or unsubstituted, or wherein at least one ring carbon atom by S, O or the corresponding heterocycle of N alternate; Alkylaryl or miscellaneous alkyl aryl, described group are respectively that single replacement is polysubstituted or unsubstituted; Aryl or heteroaryl, described group are respectively that single replacement is polysubstituted or unsubstituted, particularly styroyl, 1-adamantyl, 2-adamantyl, 1-naphthyl or 2-naphthyl, 2-, 3-or 4-pyridyl; Thiazolyl;

SR ¹⁴, R wherein ¹⁴Be selected from

Aryl or heteroaryl, described group are respectively that single replacement is polysubstituted or unsubstituted,

C (O) NR ¹⁵R ¹⁶, C (O) NR ¹⁵NR ¹⁶R ¹⁷, C (NR ¹⁵) NR ¹⁶R ¹⁷, C (S) NR ¹⁵R ¹⁶Or C (S) NR ¹⁵NR ¹⁶R ¹⁷, R wherein ¹⁵, R ¹⁶And R ¹⁷Be independently from each other

H; C ₁-C ₁₈-alkyl, C ₂-C ₁₈-alkenyl or C ₂-C ₁₈-alkynyl, described group are respectively side chains or unbranched, and single replacement is polysubstituted or unsubstituted; C ₃-C ₈-cycloalkyl, described group are saturated or undersaturated, single replace polysubstituted or unsubstituted, or wherein at least one ring carbon atom by S, O or the corresponding heterocycle of N alternate; Alkylaryl or miscellaneous alkyl aryl, described group are respectively that single replacement is polysubstituted or unsubstituted; Aryl or heteroaryl, described group are respectively that single replacement is polysubstituted or unsubstituted;

R ⁷, R ⁸, R ⁹And R ¹⁰Be independently from each other

H, F, Cl, Br, I, CN, NO ₂C ₁-C ₁₀-alkyl, C ₂-C ₁₀-alkenyl or C ₂-C ₁₀-alkynyl, described group are respectively side chains or unbranched, and single replacement is polysubstituted or unsubstituted;

OR ¹⁸, OC (O) R ¹⁸, OC (S) R ¹⁸, C (O) R ¹⁸, C (O) OR ¹⁸, C (S) R ¹⁸, C (S) OR ¹⁸, SR ¹⁸, S (O) R ¹⁸Or S (O ₂) R ¹⁸, R wherein ¹⁸Be selected from

H; C ₁-C ₁₀-alkyl, C ₂-C ₁₀-alkenyl or C ₂-C ₁₀-alkynyl, described group are respectively side chains or unbranched, and single replacement is polysubstituted or unsubstituted; C ₃-C ₈-cycloalkyl, described group are saturated or undersaturated, single replace polysubstituted or unsubstituted, or wherein at least one ring carbon atom by S, O or the corresponding heterocycle of N alternate; Alkylaryl or miscellaneous alkyl aryl, described group are respectively that single replacement is polysubstituted or unsubstituted; Aryl or heteroaryl, described group are respectively that single replacement is polysubstituted or unsubstituted;

NR ¹⁹R ²⁰, NR ¹⁹C (O) R ²⁰, C (NR ¹⁹) NR ²⁰R ²¹, NR ¹⁹C (S) R ²⁰, C (S) NR ¹⁹R ²⁰Or C (S) NR ¹⁹NR ²⁰R ²¹Or S (O ₂) NR ¹⁹R ²⁰, R wherein ¹⁹, R ²⁰And R ²¹Be independently from each other

H, O; C ₁-C ₁₈-alkyl, C ₂-C ₁₈-alkenyl or C ₂-C ₁₈-alkynyl, described group are respectively side chains or unbranched, and single replacement is polysubstituted or unsubstituted; C ₃-C ₈-cycloalkyl, described group are saturated or undersaturated, single replace polysubstituted or unsubstituted, or wherein at least one ring carbon atom by S, O or the corresponding heterocycle of N alternate; Alkylaryl or miscellaneous alkyl aryl, described group are respectively that single replacement is polysubstituted or unsubstituted; Aryl or heteroaryl, described group are respectively that single replacement is polysubstituted or unsubstituted;

Perhaps

R ¹⁹With R ²⁰Or R ²⁰With R ²¹Form C together ₃-C ₈-cycloalkyl, described group are saturated or undersaturated, single replace polysubstituted or unsubstituted, or wherein at least one ring carbon atom by S, O or the corresponding heterocycle of N alternate; Perhaps

R ⁷With R ⁸, R ⁸With R ⁹Or R ⁹With R ¹⁰Together

Formation=CR ²²-CH=CH-CH=or=CH-CR ²²=CH-CH=, wherein R ²²Be selected from

H, F, Cl, Br, I, OH or C ₁-C ₁₀-alkyl, C ₂-C ₁₀-alkenyl or C ₂-C ₁₀-alkynyl, described group are respectively side chains or unbranched, and single replacement is polysubstituted or unsubstituted.

The present invention 1,2,3,4-tetrahydroquinoline-2-carboxylic acid derivativeShow significant analgesic effect, and be the nmda antagonist of optionally attacking glycine binding site point.

For the object of the invention, the alkyl or cycloalkyl residue is meant saturated and unsaturated (but not being aromatics), side chain, unbranched and cyclic hydrocarbon, and it can be not replace or single replacement or polysubstituted.C _1-The 2-alkyl is meant C1-or C2-alkyl, C _1-3-alkyl is meant C1-, C2-or C3-alkyl, C _1-4-alkyl is meant C1-, C2-, C3-or C4-alkyl, and the C1-5-alkyl is meant C1-, C2-, C3-, C4-or C5-alkyl, C _1-6-alkyl is meant C1-, C2-, C3-, C4-, C5-or C6-alkyl, C _1-7-alkyl is meant C1-, C2-, C3-, C4-, C5-, C6-or C7-alkyl, C _1-8-alkyl is meant C1-, C2-, C3-, C4-, C5-, C6-, C7-or C8-alkyl, C _1-10-alkyl is meant C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8-, C9-or C10-alkyl, and C _1-18-alkyl is meant C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8-, C9-, C10-, C11-, C12-, C13-, C14-, C15-, C16-, C17-or C18-alkyl.In addition, C _3-4-cycloalkyl is meant C3-or C4-cycloalkyl, C _3-5-cycloalkyl is meant C3-, C4-or C5-cycloalkyl, C _3-6-cycloalkyl is meant C3-, C4-, C5-or C6-cycloalkyl, C _3-7-cycloalkyl is meant C3-, C4-, C5-, C6-or C7-cycloalkyl, C _3-8-cycloalkyl is meant C3-, C4-, C5-, C6-, C7-or C8-cycloalkyl, C _4-5-cycloalkyl is meant C4-or C5-cycloalkyl, C _4-6-cycloalkyl is meant C4-, C5-or C6-cycloalkyl, C _4-7-cycloalkyl is meant C4-, C5-, C6-or C7-cycloalkyl, C _5-6-cycloalkyl is meant C5-or C6-cycloalkyl, and C _5-7-cycloalkyl is meant C5-, C6-or C7-cycloalkyl.With regard to cycloalkyl, this term comprises that also wherein 1 or 2 carbon atom is by heteroatoms S, N or O alternate saturated cyclic alkyls.Yet the term cycloalkyl is not also particularly including there being heteroatomic list unsaturated or how unsaturated in ring, preferred single unsaturated cycloalkyl, and condition is that cycloalkyl is not an aromatic systems.Alkyl or cycloalkyl is preferably methyl, ethyl, vinyl, propyl group, allyl group (2-propenyl), 1-proyl, methylethyl, butyl, 1-methyl-propyl, 2-methyl-propyl, 1,1-dimethyl ethyl, amyl group, 1,1-dimethyl propyl, 1,2-dimethyl propyl, 2,2-dimethyl propyl, hexyl, 1-methyl amyl, cyclopropyl, 2-methyl cyclopropyl, cyclopropyl methyl, cyclobutyl, cyclopentyl, cyclopentyl-methyl, cyclohexyl, suberyl, ring octyl group and adamantyl, CHF ₂, CF ₃Or CH ₂OH, and pyrazolone, oxopyrazoline ketone, [1,4]-dioxane or dioxolane.

Should be appreciated that for the object of the invention, when describing alkyl and cycloalkyl, except as otherwise noted, otherwise replace be meant that the hydrogen residue is by F, Cl, Br, I, NH ₂, SH or OH replace, wherein " polysubstituted " residue should be meant on different and same atoms and repeatedly be replaced by identical or different substituting group, for example is substituted 3 times on identical C atom, the example is CF ₃, perhaps on different positions, being substituted 3 times, the example is-CH (OH)-CH=CH-CHCl ₂Particularly preferred substituting group is F, Cl and OH.

Should be appreciated that term (CH ₂) _3-6Be meant-CH ₂-CH ₂-CH ₂-,-CH ₂-CH ₂-CH ₂-CH ₂-,-CH ₂-CH ₂-CH ₂-CH ₂-CH ₂-and-CH ₂-CH ₂-CH ₂-CH ₂-CH ₂-CH ₂-, and term (CH ₂) _1-4Be meant-CH ₂-,-CH ₂-CH ₂-,-CH ₂-CH ₂-CH ₂-and-CH ₂-CH ₂-CH ₂-CH ₂-, or the like.

Aromatic yl residue is meant and comprises at least one aromatic ring, but do not have heteroatomic ring system in any ring.Example has phenyl, naphthyl, fluoranthene base, fluorenyl, tetralyl or indanyl, particularly 9H-fluorenyl or anthryl, and described group can be not replace or single replacement or polysubstituted.

The heteroaryl residue is meant the heterocycle system that comprises at least one unsaturated ring, wherein contains one or more heteroatomss that are selected from nitrogen, oxygen and/or sulphur, and can be single replacement or polysubstituted.The example of the heteroaryl that can mention has furans, cumarone, thiophene, thionaphthene, pyrroles, pyridine, pyrimidine, pyrazine, quinoline, isoquinoline 99.9, phthalazines, benzo [1,2,5] thiadiazoles, benzothiazole, indoles, benzotriazole, benzo dioxolane, benzo dioxane, carbazole, indoles and quinazoline.

When describing aryl and heteroaryl, the be meant aryl or the heteroaryl of replacement are replaced by following groups: R ²³, OR ²³, halogen, preferred F and/or Cl, CF ₃, CN, NO ₂, NR ²⁴R ²⁵, C _1-6-alkyl (saturated), C _1-6-alkoxyl group, C _3-8-cycloalkyloxy, C _3-8-cycloalkyl or C _2-6-alkylidene group.

In this article, radicals R ²³Represent H, C _1-10-alkyl, preferred C _1-6-alkyl, aryl or heteroaryl, or via C _1-3Aryl or heteroaryl that-alkylidene group connects, wherein these aryl and heteroaryl self can not replaced by aryl or heteroaryl,

Radicals R ²⁴And R ²⁵Can be identical or different, and represent H, C _1-10-alkyl, preferred C _1-6-alkyl, aryl, heteroaryl, or via C _1-3Aryl or heteroaryl that-alkylidene group connects, wherein these aryl and heteroaryl self can not replaced by aryl or heteroaryl,

Perhaps radicals R ²⁴And R ²⁵Represent CH together ₂CH ₂OCH ₂CH ₂, CH ₂CH ₂NR ²⁶CH ₂CH ₂Or (CH ₂) _3-6, and

Radicals R ²⁶Represent H, C _1-10-alkyl, preferred C _1-6-alkyl, aryl or heteroaryl, or representative is via C _1-3Aryl or heteroaryl that-alkylidene group connects, wherein these aryl and heteroaryl self can not replaced by aryl or heteroaryl.

Should be appreciated that term salt is meant any type of active compound of the present invention, wherein active compound is ionic species, perhaps electrically charged and with counter ion (positively charged ion or negatively charged ion) coupling, perhaps in solution.Should be appreciated that this is meant active compound of the present invention and other molecule and ionic title complex, particularly the title complex that cooperates via ionic interaction.

For the object of the invention, the physiological acceptable salt that forms with positively charged ion or alkali be meant The compounds of this invention-normally (deprotonation) acid of at least a anionic form-with at least a positively charged ion, the formed salt of preferred inorganic cation, described positively charged ion is that physiology is acceptable, is that physiology is acceptable when using in people and/or Mammals especially.The salt of basic metal and alkaline-earth metal, and have NH ₄ ⁺Salt be particularly preferred, (one) or (two) sodium salt, (one) or (two) sylvite, magnesium salts or calcium salt are the most particularly preferred.

For the object of the invention, the physiological acceptable salt that forms with negatively charged ion or acid is meant the The compounds of this invention of at least a cationic form-normally protonated, for example protonated on nitrogen-with the formed salt of at least a negatively charged ion, described negatively charged ion is that physiology is acceptable, is that physiology is acceptable when using in people and/or Mammals especially.Particularly, for the object of the invention, physiological acceptable salt is meant the salt that forms with physilogically acceptable acid, be the specific active compound and the salt of mineral acid or organic acid formation, described mineral acid or organic acid are that physiology is acceptable, are that physiology is acceptable when using in people and/or Mammals especially.The example of the physiological acceptable salt of number acid is the salt of following acid: hydrochloric acid; Hydrogen bromide; sulfuric acid; methylsulfonic acid; formic acid; acetate; oxalic acid; succsinic acid; tartrate; amygdalic acid; fumaric acid; lactic acid; citric acid; L-glutamic acid; 1; 1-dioxo-1; 2-dihydro-1; 6-benzo [d] isothiazole-3-ketone (saccharinic acid); the monomethyl sebacic acid; 5-oxo proline(Pro); hexane-1-sulfonic acid; nicotinic acid; the 2-benzaminic acid; the 3-benzaminic acid; the 4-benzaminic acid; 2; 4, the 6-trimethylbenzoic acid; (α-liponic acid; acetyl-glycine; acetylsalicylic acid; urobenzoic acid and/or aspartic acid.Hydrochloride is particularly preferred.

The application provide preferably that the formula I that is defined as follows replaces 5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-carboxylic acid derivative, wherein R ⁶Be selected from

H; C ₁-C ₁₀-alkyl, described group are not replace or single replacement or polysubstituted; Phenyl, described phenyl are not replace or single replacement or polysubstituted; Preferred H, CH ₃Or C ₂H ₅, H particularly.

The application provide preferably also that the formula I that is defined as follows replaces 5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-carboxylic acid derivative, wherein R ⁵Be selected from

H; C ₁-C ₄-alkyl, described group are side chains or unbranched, and single replacement is polysubstituted or unsubstituted; Phenyl, benzyl or styroyl, described group are that single replacement is polysubstituted or unsubstituted, preferred H, CH ₃Or C ₂H ₅, H particularly.

The application provide preferably also that the formula I that is defined as follows replaces 5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-carboxylic acid derivative, wherein R ⁷, R ⁸, R ⁹And R ¹⁰Be independently from each other

H, F, Cl, Br, I, CN, NO ₂C ₁-C ₆-alkyl, C ₂-C ₆-alkenyl or C ₂-C ₆-alkynyl, described group are respectively side chains or unbranched, and single replacement is polysubstituted or unsubstituted;

OR ¹⁸, C (O) R ¹⁸, C (O) OR ¹⁸Or SR ¹⁸, R wherein ¹⁸Be selected from

H; C ₁-C ₄-alkyl, described group are side chains or unbranched, and single replacement is polysubstituted or unsubstituted; Aryl, described group are that single replacement is polysubstituted or unsubstituted,

Preferably, R ⁷, R ⁸, R ⁹And R ¹⁰Be independently from each other

H, F, Cl, Br, I, CN; C ₁-C ₄-alkyl, described group are side chains or unbranched, and single replacement is polysubstituted or unsubstituted;

OR ¹⁸Or SR ¹⁸, R wherein ¹⁸Be selected from

H, C ₁-C ₄-alkyl, described group are side chains or unbranched, and single replacement is polysubstituted or unsubstituted; Phenyl, described phenyl are that single replacement is polysubstituted or unsubstituted,

Particularly, R ⁷, R ⁸, R ⁹And R ¹⁰Be independently from each other

H, F, Cl, Br, I, CN; CH ₃, CF ₃, the tertiary butyl, isobutyl-, OH ,-OCH ₃, OCF ₃,-SCH ₃,-O-phenyl.

Particularly preferably be in this:

R ⁷, R ⁸And R ¹⁰Be H, and R ⁹Be Cl, perhaps

R ⁷And R ⁹Be H, and R ⁸And R ¹⁰Be Cl,

Preferably, R ⁷And R ⁹Be H, and R ⁸And R ¹⁰Be Cl.

The application provide especially preferably that the formula I that is defined as follows replaces 5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-carboxylic acid derivative, wherein

R ⁵＝H，

R ⁶＝H，

R ⁷＝H，

R ⁸＝Cl，

R ⁹=H, and

R ¹⁰＝Cl。

The application provide preferably also that the formula I that is defined as follows replaces 5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-carboxylic acid derivative, wherein R ¹, R ², R ³Or R ⁴Be independently from each other

H; C ₁-C ₆-alkyl, C ₂-C ₆-alkenyl or C ₂-C ₆-alkynyl, described group are respectively side chains or unbranched, and single replacement is polysubstituted or unsubstituted;

Preferably

H, F, Cl, Br, I, CN, NH ₂, NO ₂C ₁-C ₄-alkyl, C ₂-C ₄-alkenyl or C ₂-C ₄-alkynyl, described group are respectively side chains or unbranched, and single replacement is polysubstituted or unsubstituted;

OR ¹¹, PC (O) OR ¹¹Or SR ¹¹, R wherein ¹¹Be selected from

H; C ₁-C ₄-alkyl, C ₂-C ₄-alkenyl or C ₂-C ₄-alkynyl, described group are respectively side chains or unbranched, and single replacement is polysubstituted or unsubstituted;

Particularly

H, F, Cl, Br, I, CN, NH ₂C ₁-C ₄-alkyl, described group are side chains or unbranched, and single replacement is polysubstituted or unsubstituted; SH; OR ¹¹Or C (O) OR ¹¹, R wherein ¹¹Be selected from

H; C ₁-C ₄-alkyl, described group are side chains or unbranched, and single replacement is polysubstituted or unsubstituted;

Or it is preferred especially

H, F, Cl, Br, I, CN, NH ₂, CH ₃, C ₂H ₅, n-propyl, sec.-propyl, isobutyl-, sec-butyl, normal-butyl, the tertiary butyl, CF ₃, CHF ₂, SH, OH, OCH ₃, OC ₂H ₅, C (O) OH, C (O) OCH ₃Or C (O) OC ₂H ₅

The present invention provides 5,6 of following replacement especially, 6a, and 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-carboxylic acid derivative or its salt:

-1,3-two chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid,

-1,3-two chloro-10-methoxyl groups-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid,

-1,3-two chloro-8-methyl-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid,

-1,3-two chloro-8-ethyls-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid,

-1,3-two chloro-8-fluoro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid,

-1,3,8-three chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid,

-8-bromo-1,3-two chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid,

-8-iodo-1,3-two chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid,

-1,3-two chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6, the 8-dioctyl phthalate,

-1,3-two chloro-10-methyl-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid,

-1,3-two chloro-10-fluoro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid,

-1,3,10-three chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid,

-10-bromo-1,3-two chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid,

-10-iodo-1,3-two chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid,

-1,3-two chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6, the 10-dioctyl phthalate or

-1,3-two chloro-10-cyano group-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid,

Preferred 1,3-two chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid.

Particularly preferred compound is that formula I of the present invention replaces 1,2,3,4-tetrahydroquinoline-2-carboxylic Acid derivativeFree carboxy acid or salt, described salt is its an alkali metal salt, preferred sylvite or sodium-salt form, or inorganic acid salt, the form of preferably salt hydrochlorate.

The present invention also provides 5,6 of preparation the present invention replacement, 6a, the method for the salt of 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-carboxylic acid derivative.

The multiple method that is used to prepare the parent material of Tetrahydroquinolinesas-The compounds of this invention has been described in the document:

Solid phase method (WO98/34111),

Multistep processes (WO98/42673; Bioorganic and Medicinal ChemistryLetters Vol.2, p.371,1992; Journal of Heterocyclic ChemistryVol.25, p.1831,1988; Journal of the Chemical Society, PerkinTransactions I (1989), p.2245) or

" single container " method of Louis acid catalysis (Journal of the ChemicalSociety, Chemical Communications, 1999, p.651; Journal of theAmerican Chemical Society, Vol.118, p.8977,1996).

Yet all these methods all obviously show some shortcoming.

Different with these methods, " basic skills " described herein is " single container " method trifluoroacetic acid mediation, preferred, wherein is that an aromatic amine component, an aldehyde component and an olefin component one that is rich in electronics are reacted.

Basic skills of the present invention at first prepares is R wherein ⁶=H, and other group have that a kind of formula I of above-mentioned implication replaces 5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-carboxylic acid derivative.In the method, incite somebody to action wherein R ⁷, R ⁸, R ⁹And R ¹⁰Have implication described in a kind of formula I respectively independently of one another or be provided to the formula II amino benzenes compounds of protecting group

React in 0 ℃-100 ℃ in the presence of trifluoroacetic acid with formula III glyoxylic ester or oxoethanoic acid and formula IV cumarone, wherein R ¹, R ², R ³, R ⁴And R ⁵Have implication described in a kind of formula I respectively independently of one another or be provided to protecting group.For this reaction preferably, be 0.25-12 hour between the reaction period, preferred maximum 2 hours, be reflected under the 20-40 ℃ of temperature, carry out under the preferred room temperature, and/or reaction is single container reaction.

The decisive advantage of the inventive method is that by chain (domino) reaction (form imines, carry out the azepine Diels-Alder reaction then), this method generates required system with highly selective and good yield.

Owing to need not to carry out the bonding or the removal process that for example in solid phase method, need, and need not the purify intermediates that for example in described solution chemical processes, needs, the inventive method its simply carry out and purification process aspect all shown difference.By with non-polar solvent normal hexane repetitive scrubbing for example, can obtain product with high purity largely.Otherwise they must use the column chromatography purifying.Particularly, by with non-polar solvent normal hexane washing process or for example, can obtain the pure formula I compound of diastereomer by its salt of crystallization.

Generally speaking, as preparation method's favourable form, in case the formation of formula I compound finish, promptly with can with contain required cationic or anionic alkali or acid formula I compound is changed into its salt, the salt that purifying obtained then.

Most reagent of Shi Yonging, particularly formula II, III and the commercially available acquisition of IV compound in the methods of the invention perhaps can make by simple synthesis step well known by persons skilled in the art.After basic skills, can will change into wherein R according to the product that basic skills obtains according to method known to those skilled in the art ⁶Hydrogen at first with regard to the required product of substituted formula I of the present invention.

Therefore, if required product is R wherein ⁶5 of the formula I replacement of=alkyl formyl radical, acyl group, sulfinyl and alkylsulfonyl; 6; 6a; 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-carboxylic acid derivative; in case then primitive reaction is finished; just can be with reaction product and suitable chloro-formic ester or fluorofomates, acyl chlorides, sulphinyl chlorine and SULPHURYL CHLORIDE at alkali; preferred triethylamine, pyridine or NaOH exist down; in water, dioxane/water or THF/ water mixture, under 0-20 ℃ of temperature, react (J.Org.Chem.1989; 54,5574-5580).Similarly, if required product is R wherein ⁶=C (S) NR ¹⁵R ¹⁶Formula I replace 5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-carboxylic acid derivative, in case then primitive reaction is finished, just can be with reaction product and sulfuration reagent, preferred Lawesson ' s reagent (2,4-two (4-p-methoxy-phenyl)-2,4-dithio-1,3,2,4-dithia phosphorus heterocycle butane (dithiaphosphetane)), under 30-50 ℃ of temperature, reacts in preferred THF or the toluene at organic solvent.

Perhaps, if required product is R wherein ⁶=C (O) NR ¹⁵R ¹⁶Or C (S) NR ¹⁵R ¹⁶Formula I replace 5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-carboxylic acid derivative, in case then primitive reaction is finished, just reaction product and potassium cyanate or isothiocyanic acid potassium can be reacted in being up under 100 ℃ the temperature in water, perhaps with organic isocyanate or lsothiocyanates at alcohol, react in being up under the boiling temperature in particular methanol, ethanol or the Virahol.In addition, if required product is R wherein ⁶=C (NR ¹⁵) NR ¹⁶R ¹⁷Formula I replace 5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-carboxylic acid derivative, in case then primitive reaction is finished, just can be under alkaline condition with reaction product and O-methyl-isourea class or S-methyl-isothiourea class, preferably in the ethanol of NaOH or KOH or methanol solution, under 20-50 ℃ of temperature, react.

In addition, if required product is R wherein ⁶=C (O) NR ¹⁵R ¹⁶Formula I replace 5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-carboxylic acid derivative in case then primitive reaction is finished, can also react reaction product and 2-acetone semicarbazone in water/Glacial acetic acid under 30-60 ℃ of temperature.

Similarly, if required product is R wherein ⁶=C (S) NR ¹⁵R ¹⁶Formula I replace 5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-carboxylic acid derivative, in case then primitive reaction is finished, just can be with reaction product and CS ₂Under 30-60 ℃ of temperature, react in water/NaOH with the hydrazine class.

As the last possibility that can mention in this respect, if required product is R wherein ⁶5 of the formula I replacement of=alkyl, benzyl or styroyl, 6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-carboxylic acid derivative, in case then primitive reaction is finished, just can be with reaction product and suitable alkylogen, benzyl halide or styroyl halogen and suitable alkali, preferred sodium hydride or potassium tert.-butoxide for example react (J.Org.Chem.1947 in the ethanol at solvent under 0-100 ℃ of temperature, 12,760; Zh.Obshch.Khim.1942,12,418).

Under a lot of above-mentioned reaction conditionss, OH, SH and NH ₂Unwanted side reaction might take place in group.Therefore, protecting group is provided preferably for described group, perhaps, for NH ₂, it is used NO ₂Replace, and before the purifying end product, remove protecting group or NO ₂The group reduction.So the application also provides the modification of aforesaid method, wherein in starting compound, has an OH group at least by OSi (Ph) ₂The tertiary butyl replaces, and has at least a SH by S-methoxy-benzyl to be replaced, and/or at least one NH ₂By NO ₂Replace, and before the purifying end product, in tetrahydrofuran (THF) with tetrabutylammonium with at least one, preferred all OSi (Ph) ₂The tertiary butyl is removed, and/or with the metal amino thing, preferred sodium amide is with at least one, and preferably all are removed methoxy-benzyl, and/or with at least one, preferably all NO ₂Be reduced into NH ₂

In addition, in some cases, carboxylic acid or thiocarboxylic acid group are unstable under reaction conditions, and preferred like this its methyl esters that uses in reaction is used the product saponification with method under 40 ℃ of-60 ℃ of temperature of KOH solution or NaOH solution then in methyl alcohol.Therefore, the present invention also provides the modification of aforesaid method, wherein before the purifying end product, uses KOH solution or NaOH solution in 0 ℃-100 ℃ in methyl alcohol or ethanol, will have at least one C (O) OCH under preferred 40 ℃ of-60 ℃ of temperature ₃, OC (O) OCH ₃And/or C (S) OCH ₃The product saponification of the method for group.

Therefore, for basic skills of the present invention, when preparing wherein R ⁵The formula I of=H replace 5,6, when 6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-carboxylic acid derivative, use wherein R ⁵≠ H, and R ⁵Be preferably alkyl, particularly CH ₃And C ₂H ₅The formula III starting compound be favourable.According to basic skills and possible subsequently reaction, with suitable alkali, preferred NaOH or KOH in ethanol or methyl alcohol in 0-100 ℃, under preferred 40 ℃ of-60 ℃ of temperature with the reaction product saponification (Organikum, 1990, p.418).

In order to prepare the salt, particularly physiological acceptable salt that forms with positively charged ion or alkali, use following method: with 1 equivalent formula I compound, preferred imino-acid or carboxylic acid, particularly R wherein ³The formula I compound of=H is suspended in the less water, adds 1 equivalent 1N alkali aqueous solution, for example NaOH or KOH.If solvability is not good, drip methyl alcohol until reaching dissolving fully.After stirring at room, this mixture is evaporated in Rotary Evaporators, surplus solution is freezing under low temperature in Virahol/dry ice mixture, and freeze-drying.Obtained is salt, particular certain cancers or the sylvite of the on the whole salt of colorless solid, particularly imino-acid or carboxylic acid.Perhaps, also can prepare sylvite or sodium salt (E.D.Laganis, B.L.Chenard with trimethyl silane potassium alcoholate or trimethyl silicane sodium alkoxide; Tetrahedron Letter s25,5831-5834 (1984)).In this case, under nitrogen atmosphere, trimethyl silane potassium alcoholate or trimethyl silicane sodium alkoxide are dissolved in the organic solvent (for example methylene dichloride, toluene, THF) disposable adding ester or acid.This reaction mixture in stirring at room 2 hours or longer time, is filtered.With on the whole colourless solids wash, and vacuum-drying.Obtained as solid sylvite or sodium salt.

5,6 of the present invention's replacement, 6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-carboxylic acid derivative is safe on toxicology, they are suitable for use as the medicine activity component in the pharmaceutical preparation like this.

The present invention also provides pharmaceutical preparation, contain wherein that formula I at least a of the present invention as active ingredient replaces 5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-carboxylic acid derivative, described compound is the form of its preparation, or the form of its acid or alkali, or the form of its salt, particularly physiological acceptable salt, or the form of its solvate, particularly hydrate; The form of its physiological acceptable salt that forms with positively charged ion or alkali or with negatively charged ion or acid particularly; Can choose wantonly and be its racemic modification form, the steric isomer that it is pure, particularly enantiomorph or diastereomer form, or steric isomer, particularly enantiomorph or diastereomer are with the form of mixtures of any required mixed ratio; Optional suitable additive and/or auxiliary and/or the optional other active ingredient of containing of described pharmaceutical preparation.

Pharmaceutical preparation of the present invention can be with the form administration of injection solution, drops or juice agent, semisolid dosage form administration as granula, tablet, pill, patch, capsule, application or aerosol form, and except 5 of at least a the present invention's replacement, 6,6a, beyond 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-carboxylic acid derivative, according to pharmaceutical dosage form, optional vehicle, weighting agent, solvent, thinner, tinting material and/or the tackiness agent of also comprising.The selection of auxiliary and consumption thereof depend on that pharmaceutical preparation is oral administration, oral administration, parenteral administration, intravenous administration, intraperitoneal administration, intradermal administration, intramuscular administration, intranasal administration, cheek administration, rectal administration or topical, for example to the infection site topical of skin, mucous membrane or eyes.The preparation of tablet, coated tablet, capsule, granula, drops, juice agent and syrup form is suitable for oral administration, and solution, suspension, the drying agent that is easy to prepare again and sprays are suitable for parenteral administration, topical and inhalation.With solubilized form in the storage storehouse or the present invention in application replace 5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-carboxylic acid derivative (the optional dermal osmosis accelerator that adds) are the examples of suitable percutaneous drug administration preparation.Can discharge 5,6 of the present invention's replacement, 6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-carboxylic acid derivative in the mode that postpones by preparation oral or percutaneous dosing.Active ingredient becomes patient's the dosage severity according to patient's body weight, administering mode, indication and illness.Usually use 5,6 of at least a formula I replacement of the present invention of 2-500mg/kg, 6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-carboxylic acid derivative.

5 of the present invention's replacement, 6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-carboxylic acid derivative can be preferred for treating pain, particularly chronic pain and neuropathic pain, and migraine, therefore, the present invention also provides 5,6 of at least a formula I replacement of the present invention, 6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-carboxylic acid derivative is used for the treatment of pain in preparation, particularly neuropathic pain and/or chronic pain, and/or be used for the treatment of application in the migrainous pharmaceutical preparation, wherein said compound is the form of its preparation, or the form of its acid or alkali, or the form of its salt, particularly physiological acceptable salt, or the form of its solvate, particularly hydrate; The form of its physiological acceptable salt that forms with positively charged ion or alkali or with negatively charged ion or acid particularly; Can choose wantonly and be its racemic modification form, the steric isomer that it is pure, particularly enantiomorph or diastereomer form, or steric isomer, particularly enantiomorph or diastereomer are with the form of mixtures of any required mixed ratio.

Therefore other application is based on the avidity to nmda receptor, because known nmda antagonist has neuroprotective especially, and is highly suitable for treating and follows for example clinical symptom of Parkinson's disease and Huntington Chorea etc. of neurodegeneration and nerve injury.Other indication of nmda antagonist of the present invention is epilepsy, glaucoma, osteoporosis, the ear Withrawal symptom of poisoning, follow alcohol and/or drug abuse, apoplexy and cerebral ischemia, cerebral infarction, cerebral edema, hypoxemia, the anoxia relevant with apoplexy and is used for anxiety and anesthesia.Therefore, the present invention also provides 5 of at least a formula I replacement of the present invention, 6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-carboxylic acid derivative is used for the treatment of/prevents the application in the pharmaceutical preparation of following disease in preparation: epilepsy, Parkinson's disease, Huntington Chorea, glaucoma, ear is poisoned, follow the Withrawal symptom of alcohol and/or drug abuse, apoplexy, cerebral ischemia, cerebral infarction, cerebral edema, hypoxemia, anoxia and/or be used for anxiety and/or anesthesia, wherein said compound is the form of its preparation, or the form of its acid or alkali, or its salt, the form of physiological acceptable salt particularly, or the form of its solvate, particularly hydrate; The form of its physiological acceptable salt that forms with positively charged ion or alkali or with negatively charged ion or acid particularly; Can choose wantonly and be its racemic modification form, the steric isomer that it is pure, particularly enantiomorph or diastereomer form, or steric isomer, particularly enantiomorph or diastereomer are with the form of mixtures of any required mixed ratio.

Be surprised to find, 5,6 of the present invention's replacement, 6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-carboxylic acid derivative also is very suitable for other indication, particularly is suitable for treating the urinary incontinence, itch, tinnitus and/or diarrhoea.Therefore, the application also provides 5 of at least a formula I replacement of the present invention, 6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-carboxylic acid derivative is used for the treatment of application in the pharmaceutical preparation of the urinary incontinence, itch, tinnitus and/or diarrhoea in preparation, wherein said compound is the form of its preparation, or the form of its acid or alkali, or the form of its salt, particularly physiological acceptable salt, or the form of its solvate, particularly hydrate; The form of its physiological acceptable salt that forms with positively charged ion or alkali or with negatively charged ion or acid particularly; Can choose wantonly and be its racemic modification form, the steric isomer that it is pure, particularly enantiomorph or diastereomer form, or steric isomer, particularly enantiomorph or diastereomer are with the form of mixtures of any required mixed ratio.

Yet The compounds of this invention can also be used for other indication effectively.Therefore, the application also provides 5 of at least a formula I replacement of the present invention, 6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-carboxylic acid derivative is used for the treatment of/prevents the application in the pharmaceutical preparation of following illness in preparation: schizophrenia, Alzheimer, increase the psychosis (psychoses) that causes owing to amino acid levels, the AIDS dementia, encephalomyelitis, Tourette ' s syndrome, suffocate term, inflammatory and transformation reactions, dysthymia disorders, medicine and/or alcohol abuse, gastritis, diabetes, cardiovascular diseases, respiratory disease, cough and/or psychosis, wherein said compound is the form of its preparation, or the form of its acid or alkali, or its salt, the form of physiological acceptable salt particularly, or the form of its solvate, particularly hydrate; The form of its physiological acceptable salt that forms with positively charged ion or alkali or with negatively charged ion or acid particularly; Can choose wantonly and be its racemic modification form, the steric isomer that it is pure, particularly enantiomorph or diastereomer form, or steric isomer, particularly enantiomorph or diastereomer are with the form of mixtures of any required mixed ratio.

The present invention also provides treatment to need medical related indication non-human mammal of treatment or people's method, comprise that the formula I of the present invention of administering therapeutic effective dose replaces 5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-carboxylic acid derivative or pharmaceutical preparation of the present invention, wherein said compound is the form of its preparation, or the form of its acid or alkali, or the form of its salt, particularly physiological acceptable salt, or the form of its solvate, particularly hydrate; The form of its physiological acceptable salt that forms with positively charged ion or alkali or with negatively charged ion or acid particularly; Can choose wantonly and be its racemic modification form, the steric isomer that it is pure, particularly enantiomorph or diastereomer form, or steric isomer, particularly enantiomorph or diastereomer are with the form of mixtures of any required mixed ratio.The present invention also is particularly related to the following correlation method of purpose: treatment pain, particularly neuropathic pain and/or chronic pain and/or the treatment migraine, the treatment urinary incontinence, itch, tinnitus and/or diarrhoea, treatment/prevention epilepsy, Parkinson's disease, Huntington Chorea, glaucoma, osteoporosis, ear is poisoned, follow the Withrawal symptom of alcohol and/or drug abuse, apoplexy, cerebral ischemia, cerebral infarction, cerebral edema, hypoxemia, anoxia and/or be used for anxiety and/or anesthesia, or treatment/prevention schizophrenia, Alzheimer, increase the psychosis that causes owing to amino acid levels, the AIDS dementia, encephalomyelitis, Tourette ' s syndrome, suffocate term, inflammatory and transformation reactions, dysthymia disorders, medicine and/or alcohol abuse, gastritis, diabetes, cardiovascular diseases, respiratory disease, cough and/or psychosis.The following example illustrates the present invention, rather than restriction the present invention.

Embodiment

The effectiveness test that the following example illustrates The compounds of this invention and preparation thereof and carries out with described compound.

Use following general note:

Used chemical reagent and solvent be available from traditional supplier (Acros, Avocado, Aldrich, Fluka, Lancaster, Maybridge, Merck, Sigma, TCI etc.), or by conventional preparation method's synthetic well known by persons skilled in the art.Particularly, other compound of some of some benzofuran compound and use is to make up the structure synthetic with known synthetic method as synthesizing before following basic synthesizing.Thin-layer chromatography is to use available from E.Merck, and the silica gel that the overlays 60 F 254 HPTLC plates of Darmstadt carry out.The productive rate of prepared compound is not optimized.

Analysis is undertaken by the ESI mass spectrum.

Give compound number, the value in the bracket is corresponding with the numbering of given compound in principle.

Embodiment 0

Basic skills

A) in room temperature under stirring, every kind of anils of 1 equivalent and trifluoroacetic acid are dissolved in the 6ml/mmol acetonitrile, add 1.1 equivalent glyoxylic acid ethyl esters (50% toluene solution) or 1.1 equivalent oxoethanoic acid monohydrates then.After 10 minutes, add 3 equivalent cumarone compositions, by thin-layer chromatography monitoring reaction process (the mobile phase solvent system is an ether/hexane, 1: 1).This finishes (TLC monitoring) after being reflected at 2 hours.This reaction mixture and excessive saturated sodium bicarbonate aqueous solution are merged, with ether with organic extractant phase 3 times.Water to neutral, is used dried over mgso with the organic phase washing, filters, and with the ether washing, after the evaporation, separates by recrystallization or silica gel chromatography.Determine 5,6 by the ESI mass spectrum, 6a, the feature of 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-manthanoate.

B) optionally prepare free 5,6 subsequently, 6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid class

With above-mentioned 5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-manthanoate (1 equivalent) is dissolved in the 4ml/mmol ethanol, and merges with 1.2 equivalent 6N aqueous sodium hydroxide solutions under stirring in room temperature.By thin-layer chromatography monitoring ester saponification process (the mobile phase solvent system is an ether/hexane, 1: 1).This finishes (TLC monitoring) after being reflected at 30 minutes.This reaction mixture is evaporated in Rotary Evaporators, be dissolved in again in about 10ml water, be adjusted to pH1 with 32%HCl.With this aqueous solution extraction 5 times, use dried over mgso with ether, then evaporation.

Automated method

Agitator is placed in the round bottom Glass tubing (diameter 16mm, length 125mm) with screw thread, use screw-cap this Glass tubing sealing with partition.This Glass tubing is placed adjusted to 20 ℃ whipping appts.Add following reagent successively with volumetric pipette then:

The 1ml trifluoroacetic acid solution, 0.1M and the solution of 0.1M aniline composition in acetonitrile; The solution of 1ml 0.11M aldehyde in acetonitrile; The solution of 1ml 0.3M cumarone in acetonitrile.

For this method, aldehyde should be meant oxoethanoic acid and glyoxylic ester, preferred alkyl ester, particularly ethyl ester or methyl esters.This reaction mixture was stirred 10 hours in 20 ℃ in a whipping appts.Then this reaction soln is filtered.With 7.5% sodium hydrogen carbonate solution that is 1.5ml at every turn this Glass tubing is washed 2 times.

This reaction mixture and 2ml ethyl acetate are merged on vortice, and shake.This mixture is centrifugal simply to form the phase border in centrifuge tube.Survey the phase border by optical instrument, take out organic phase with volumetric pipette.In the step of following, water is merged with the 2ml ethyl acetate once more, shake, centrifugal, take out organic phase with transfer pipet.Organic phase is merged, use 2.4g MgSO ₄(ball) drying.In vacuum centrifuge, remove and desolvate.

Determine to dissociate 5,6,6a, the feature of 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid or ester by the ESI mass spectrum.

In principle, for R ³The compound of ≠ H automatically and after the standard basic skills, can carry out saponification according to method known to those skilled in the art, for example use KOH solution or NaOH solution in methyl alcohol or ethanol in 0 ℃-100 ℃, preferred 40 ℃-60 ℃ are carried out saponification.

Embodiment 1

1,3-two chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid (1)

According to the basic skills of embodiment 0, with 3,5-dichlorphenamide bulk powder, glyoxylic acid ethyl ester and unsubstituted cumarone react, and with the saponification of gained ester, have obtained compound 1 then.

Embodiment 2

1,3-two chloro-10-methoxyl groups-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid (2)

According to the basic skills of embodiment 0, with 3,5-dichlorphenamide bulk powder, glyoxylic acid ethyl ester and 5-methoxyl group benzo furans react, and with the saponification of gained ester, have obtained compound 2 then.

Embodiment 3

1,3-two chloro-8-methyl-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid (3)

According to the basic skills of embodiment 0, with 3,5-dichlorphenamide bulk powder, glyoxylic acid ethyl ester and 7-methyl cumarone react, and with the saponification of gained ester, have obtained compound 3 then.

Embodiment 4

1,3-two chloro-8-ethyls-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid (4)

According to the basic skills of embodiment 0, with 3,5-dichlorphenamide bulk powder, glyoxylic acid ethyl ester and 7-ethyl benzofuran react, and with the saponification of gained ether, have obtained compound 4 then.

Embodiment 5

1,3-two chloro-8-ethyls-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid (5)

According to the basic skills of embodiment 0, with 3,5-dichlorphenamide bulk powder, glyoxylic acid ethyl ester and 7-methoxyl group benzo furans react, and with the saponification of gained ester, have obtained compound 5 then.

Embodiment 6

1,3-two chloro-8-fluoro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid (6)

According to the basic skills of embodiment 0, with 3,5-dichlorphenamide bulk powder, glyoxylic acid ethyl ester and 7-fluorobenzene and furans react, and with the saponification of gained ester, have obtained compound 6 then.

Embodiment 7

1,3,8-three chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid (7)

According to the basic skills of embodiment 0, with 3,5-dichlorphenamide bulk powder, glyoxylic acid ethyl ester and 7-chlorobenzene and furans react, and with the saponification of gained ester, have obtained compound 7 then.

Embodiment 8

8-bromo-1,3-two chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid (8)

According to the basic skills of embodiment 0, with 3,5-dichlorphenamide bulk powder, glyoxylic acid ethyl ester and 7-bromobenzene and furans react, and with the saponification of gained ester, have obtained compound 8 then.

Embodiment 9

8-iodo-1,3-two chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid (9)

According to the basic skills of embodiment 0, with 3,5-dichlorphenamide bulk powder, glyoxylic acid ethyl ester and 7-iodobenzene and furans react, and with the saponification of gained ester, have obtained compound 9 then.

Embodiment 10

1,3-two chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6,8-dioctyl phthalate (10)

According to the basic skills of embodiment 0, with 3,5-dichlorphenamide bulk powder, glyoxylic acid ethyl ester and cumarone-7-formic acid reacts, and with the saponification of gained ester, has obtained compound 10 then.

Embodiment 11

1,3-two chloro-10-methyl-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid (11)

According to the basic skills of embodiment 0, with 3,5-dichlorphenamide bulk powder, glyoxylic acid ethyl ester and 5-methyl cumarone react, and with the saponification of gained ester, have obtained compound 11 then.

Embodiment 12

1,3-two chloro-10-fluoro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid (12)

According to the basic skills of embodiment 0, with 3,5-dichlorphenamide bulk powder, glyoxylic acid ethyl ester and 5-fluorobenzene and furans react, and with the saponification of gained ester, have obtained compound 12 then.

Embodiment 13

1,3,10-three chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid (13)

According to the basic skills of embodiment 0, with 3,5-dichlorphenamide bulk powder, glyoxylic acid ethyl ester and 5-chlorobenzene and furans react, and with the saponification of gained ester, have obtained compound 13 then.

Embodiment 14

10-bromo-1,3-two chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid (14)

According to the basic skills of embodiment 0, with 3,5-dichlorphenamide bulk powder, glyoxylic acid ethyl ester and 5-bromobenzene and furans react, and with the saponification of gained ester, have obtained compound 14 then.

Embodiment 15

10-iodo-1,3-two chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid (15)

According to the basic skills of embodiment 0, with 3,5-dichlorphenamide bulk powder, glyoxylic acid ethyl ester and 5-iodobenzene and furans react, and with the saponification of gained ester, have obtained compound 15 then.

Embodiment 16

1,3-two chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6,10-dioctyl phthalate (16)

According to the basic skills of embodiment 0, with 3,5-dichlorphenamide bulk powder, glyoxylic acid ethyl ester and cumarone-5-formic acid reacts, and with the saponification of gained ester, has obtained compound 16 then.

Embodiment 17

1,3-two chloro-10-cyano group-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid (17)

According to the basic skills of embodiment 0, with 3,5-dichlorphenamide bulk powder, glyoxylic acid ethyl ester and 5-cyano group cumarone react, and with the saponification of gained ester, have obtained compound 17 then.

Embodiment 18: the compound of usefulness embodiment 1-17 prepares the general method of the salt that forms with positively charged ion as an example

With the compound of one of 1 equivalent embodiment 1-17, preferred imino-acid is suspended in the less water, adds 1 equivalent 1N alkali aqueous solution, preferred NaOH or KOH.If solvability is not good, drip methyl alcohol until reaching dissolving fully., after 30 minutes this mixture is evaporated in Rotary Evaporators in stirring at room, with surplus solution in Virahol/dry ice mixture in-60 ℃ freezing, and freeze-drying.Obtained is the on the whole salt of the salt of colorless solid, particularly imino-acid, particular certain cancers or sylvite.

Perhaps, also can prepare sylvite or sodium salt (E.D.Laganis, B.L.Chenard with trimethyl silane potassium alcoholate or trimethyl silicane sodium alkoxide; Tetrahedron Letters 25,5831-5834 (1984)).Under nitrogen atmosphere, trimethyl silane potassium alcoholate or trimethyl silicane sodium alkoxide are dissolved in the organic solvent (methylene dichloride, toluene, THF) disposable adding ester or acid.This reaction mixture stirring at room 4 hours, is filtered.To on the whole colourless solids wash with ether, and vacuum-drying.Obtained as solid sylvite or sodium salt.

The compound of embodiment 19-35 is the sodium salt of the compound 1-17 that makes according to these exemplary methods, and the compound of embodiment 36-52 is the sylvite that correspondingly makes.

Embodiment 19

1,3-two chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formate; Sodium salt (19)

Compound 19 is that the method by embodiment 18 is made by compound 1.

Embodiment 20

1,3-two chloro-10-methoxyl groups-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formate; Sodium salt (20)

Compound 20 is that the method by embodiment 18 is made by compound 2.

Embodiment 21

1,3-two chloro-8-methyl-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formate; Sodium salt (21)

Compound 21 is that the method by embodiment 18 is made by compound 3.

Embodiment 22

1,3-two chloro-8-ethyls-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formate; Sodium salt (22)

Compound 22 is that the method by embodiment 18 is made by compound 4.

Embodiment 23

1,3-two chloro-8-ethyls-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formate; Sodium salt (23)

Compound 23 is that the method by embodiment 18 is made by compound 5.

Embodiment 24

1,3-two chloro-8-fluoro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formate; Sodium salt (24)

Compound 24 is that the method by embodiment 18 is made by compound 6.

Embodiment 25

1,3,8-three chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formate; Sodium salt (25)

Compound 25 is that the method by embodiment 18 is made by compound 7.

Embodiment 26

8-bromo-1,3-two chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formate; Sodium salt (26)

Compound 26 is that the method by embodiment 18 is made by compound 8.

Embodiment 27

8-iodo-1,3-two chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formate; Sodium salt (27)

Compound 27 is that the method by embodiment 18 is made by compound 9.

Embodiment 28

1,3-two chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6,8-diformate; Disodium salt (28)

Compound 28 is that the method by embodiment 18 is made by compound 10.

Embodiment 29

1,3-two chloro-10-methyl-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formate; Sodium salt (29)

Compound 29 is that the method by embodiment 18 is made by compound 11.

Embodiment 30

1,3-two chloro-10-fluoro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formate; Sodium salt (30)

Compound 30 is that the method by embodiment 18 is made by compound 12.

Embodiment 31

1,3,10-three chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formate; Sodium salt (31)

Compound 31 is that the method by embodiment 18 is made by compound 13.

Embodiment 32

10-bromo-1,3-two chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formate; Sodium salt (32)

Compound 32 is that the method by embodiment 18 is made by compound 14.

Embodiment 33

10-iodo-1,3-two chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formate; Sodium salt (33)

Compound 33 is that the method by embodiment 18 is made by compound 15.

Embodiment 34

1,3-two chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6,10-diformate; Disodium salt (34)

Compound 34 is that the method by embodiment 18 is made by compound 16.

Embodiment 35

1,3-two chloro-10-cyano group-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formate; Sodium salt (35)

Compound 35 is that the method by embodiment 18 is made by compound 17.

Embodiment 36

1,3-two chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formate; Sylvite (36)

Compound 36 is that the method by embodiment 18 is made by compound 1.

Embodiment 37

1,3-two chloro-10-methoxyl groups-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formate; Sylvite (37)

Compound 37 is that the method by embodiment 18 is made by compound 2.

Embodiment 38

1,3-two chloro-8-methyl-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formate; Sylvite (38)

Compound 38 is that the method by embodiment 18 is made by compound 3.

Embodiment 39

1,3-two chloro-8-ethyls-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formate; Sylvite (39)

Compound 39 is that the method by embodiment 18 is made by compound 4.

Embodiment 40

1,3-two chloro-8-ethyls-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formate; Sylvite (40)

Compound 40 is that the method by embodiment 18 is made by compound 5.

Embodiment 41

1,3-two chloro-8-fluoro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formate; Sylvite (41)

Compound 41 is that the method by embodiment 18 is made by compound 6.

Embodiment 42

1,3,8-three chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formate; Sylvite (42)

Compound 42 is that the method by embodiment 18 is made by compound 7.

Embodiment 43

8-bromo-1,3-two chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formate; Sylvite (43)

Compound 43 is that the method by embodiment 18 is made by compound 8.

Embodiment 44

8-iodo-1,3-two chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formate; Sylvite (44)

Compound 44 is that the method by embodiment 18 is made by compound 9.

Embodiment 45

1,3-two chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6,8-diformate; Di-potassium (45)

Compound 45 is that the method by embodiment 18 is made by compound 10.

Embodiment 46

1,3-two chloro-10-methyl-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formate; Sylvite (46)

Compound 46 is that the method by embodiment 18 is made by compound 11.

Embodiment 47

1,3-two chloro-10-fluoro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formate; Sylvite (47)

Compound 47 is that the method by embodiment 18 is made by compound 12.

Embodiment 48

1,3,10-three chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formate; Sylvite (48)

Compound 31 is that the method by embodiment 18 is made by compound 13.

Embodiment 49

10-bromo-1,3-two chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formate; Sylvite (49)

Compound 49 is that the method by embodiment 18 is made by compound 14.

Embodiment 50

10-iodo-1,3-two chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formate; Sylvite (50)

Compound 50 is that the method by embodiment 18 is made by compound 15.

Embodiment 51

1,3-two chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6,10-diformate; Di-potassium (51)

Compound 51 is that the method by embodiment 18 is made by compound 16.

Embodiment 52

1,3-two chloro-10-cyano group-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formate; Sylvite (52)

Compound 52 is that the method by embodiment 18 is made by compound 17.

Embodiment 53: the hydrochloride of the compound of usefulness embodiment 1-17 prepares the general method of the salt that forms with negatively charged ion as an example

The compound of one of the 1 equivalent embodiment 1-17 ratio with the about 10ml solvent of every gram material is dissolved in the 2-butanone.The water that adds half molar equivalent then adds the chlorine trimethyl silyl of 1.1 molar equivalents afterwards.This mixture stirring is spent the night.If when being cooled to about 4 ℃, do not form any hydrochloride, precipitation mixture is resuspended in the water of two volumes, with a small amount of ether washing 3 times, water alkalizes with a small amount of about 30% sodium hydroxide solution, with extracted with diethyl ether 3 times (" soda acid extraction ").The extraction liquid that these are final merges, and carries out another time hydrochloride precipitation.

The compound of embodiment 54-70 is the hydrochloride of the compound 1-17 that makes according to these exemplary methods.

Embodiment 54

1,3-two chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid; Hydrochloride (54)

Compound 54 is that the method by embodiment 53 is made by compound 1.

Embodiment 55

1,3-two chloro-10-methoxyl groups-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid; Hydrochloride (55)

Compound 55 is that the method by embodiment 53 is made by compound 2.

Embodiment 56

1,3-two chloro-8-methyl-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid; Hydrochloride (56)

Compound 56 is that the method by embodiment 53 is made by compound 3.

Embodiment 57

1,3-two chloro-8-ethyls-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid; Hydrochloride (57)

Compound 57 is that the method by embodiment 53 is made by compound 4.

Embodiment 58

1,3-two chloro-8-ethyls-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid; Hydrochloride (58)

Compound 58 is that the method by embodiment 53 is made by compound 5.

Embodiment 59

1,3-two chloro-8-fluoro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid; Hydrochloride (59)

Compound 59 is that the method by embodiment 53 is made by compound 6.

Embodiment 60

1,3,8-three chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid; Hydrochloride (60)

Compound 60 is that the method by embodiment 53 is made by compound 7.

Embodiment 61

8-bromo-1,3-two chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid; Hydrochloride (61)

Compound 61 is that the method by embodiment 53 is made by compound 8.

Embodiment 62

8-iodo-1,3-two chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid; Hydrochloride (62)

Compound 62 is that the method by embodiment 53 is made by compound 9.

Embodiment 63

1,3-two chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6,8-dioctyl phthalate; Hydrochloride (63)

Compound 63 is that the method by embodiment 53 is made by compound 10.

Embodiment 64

1,3-two chloro-10-methyl-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid; Hydrochloride (64)

Compound 64 is that the method by embodiment 53 is made by compound 11.

Embodiment 65

1,3-two chloro-10-fluoro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid; Hydrochloride (65)

Compound 65 is that the method by embodiment 53 is made by compound 12.

Embodiment 66

1,3,10-three chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid; Hydrochloride (66)

Compound 66 is that the method by embodiment 53 is made by compound 13.

Embodiment 67

10-bromo-1,3-two chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid; Hydrochloride (67)

Compound 67 is that the method by embodiment 53 is made by compound 14.

Embodiment 68

10-iodo-1,3-two chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid; Hydrochloride (68)

Compound 68 is that the method by embodiment 53 is made by compound 15.

Embodiment 69

1,3-two chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6,10-dioctyl phthalate; Hydrochloride (69)

Compound 69 is that the method by embodiment 53 is made by compound 16.

Embodiment 70

1,3-two chloro-10-cyano group-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid; Hydrochloride (70)

Compound 70 is that the method by embodiment 53 is made by compound 17.

Embodiment 71

Receptors bind (the glycine binding site point of nmda receptor channel)

Be used to measure the test [B.M.Baron of formula I compound of the present invention with meninx homogenate (deriving from the cortex of male Wistar rat brain and the homogenate of hippocampus) to the avidity of the glycine binding site point of nmda receptor channel, B.W.Siegel, B.L.Harrison, R.S.Gross, C.Hawes and P.Towers, Journal of Pharmacology andExperimental Therapeutics, Vol.279, p.62,1996].

For this, cortex and hippocampus are scaled off from the rat brain that newly cuts off, in ice-cooled following at 5mmol/l TRIS-acetate buffer, 0.32mol/l (the fresh weight of 10ml/g) uses Potter homogenizer (Braun/Melsungen among the sucrose pH7.4, with 500rpm 10 travel of piston) homogenize, then 4 ℃ with 1, centrifugal 10 minutes of 000g.Collect first portion of supernatant liquor, at the ice-cooled 5mmol/l TRIS-acetate buffer of using down, 0.32mol/1 sucrose pH7.4 (the initial fresh weight of 5ml/g) will precipitate homogenize once more by Potter homogenizer (with 500rpm 10 travel of piston), 4 ℃ with 1, centrifugal 10 minutes of 000g.The centrifugal supernatant liquor merges with deriving from for the first time with the gained supernatant liquor, 4 ℃ with 17, centrifugal 20 minutes of 000g.Discard the centrifugal supernatant liquor that obtains of this time, film precipitated resuspended (the initial fresh weight of 20ml/g) with 5mmol/l TRIS-acetate buffer pH8.0, with 10 travel of piston with the 500rpm homogenize.Then film homogenize thing was cultivated 1 hour at 4 ℃, 4 ℃ with 50, centrifugal 30 minutes of 000g.Abandoning supernatant will contain the sedimentary centrifuge tube sealing of film with Parafilm, and will be freezing 24 hours at-20 ℃.At ensuing one day, the film throw out is melted, use the 5mmol/lTRIS-acetate buffer, 0.1% saponin(e (w/v) pH7.0 resuspended (the initial fresh weight of 10ml/g), with 10 travel of piston with the 500rpm homogenize, then 4 ℃ with 50, centrifugal 20 minutes of 000g.Discard the gained supernatant liquor, the throw out 5mmol/l TRIS-acetate buffer pH7.0 resuspended (the initial fresh weight of about 2ml/g) with small volume uses 10 travel of piston with the 500rpm homogenize once more.Measure after the protein content, with 5mmol/l TRIS-acetate buffer pH7.0 film homogenize thing being adjusted to protein concentration is 10mg albumen/ml, freezing until beginning test with sample aliquot.In order to carry out receptor binding assays, sample aliquot is melted, carry out dilution in 1: 10 with 5mmol/l TRIS-acetate buffer pH7.0, ice-cooled down by Potter homogenizer (with 500rpm 10 travel of piston) with 10 travel of piston with the 500rpm homogenize, 4 ℃ with 55, centrifugal 60 minutes of 000g.Abandoning supernatant, with ice-cold 50mmol/lTRIS-acetate buffer pH7.0 the film throw out being adjusted to protein concentration is 1mg/ml, uses 10 travel of piston with the 500rpm homogenize once more, keeps with the suspension state in ice bath, stirs on magnetic stirrer simultaneously.(use in receptor binding assays by the amount of 0.1mg albumen in final mixture/ml) with 100 μ l/1ml test mixtures for this film homogenize thing.In in conjunction with test, use 50mmol/l TRIS-acetate buffer pH7.0 as damping fluid, use 1nmol/l ( ³H)-MDL105.519 (people such as B.M.Baron, 1996) is as radioligand.In the presence of the 1mmol/l glycine, measure the level of non-specific binding.

In other several the test mixtures, add the The compounds of this invention of series concentration, determine on the glycine binding site point of nmda receptor channel specificity bonded radioligand by replacement amount.In triplicate every part of test mixture was cultivated 120 minutes at 4 ℃, gathered in the crops by filtering then, to measure and film homogenize thing bonded radioactivity via glass fibre filter pad (GF/B).After adding scintillator, in beta-counter, measure the radioactivity that is retained on the glass fibre filter.

According to the law of mass action, calculate with IC by non-linear regression ₅₀The The compounds of this invention of value (radioligand when 50% is by the concentration when its specific binding site is replaced) expression is to the avidity of the glycine binding site point of nmda receptor channel, transform (use Cheng-Prussoff formula) after, with K _iValue (mean values of 3 independent experiments) is shown in Table 1, perhaps as being represented by the per-cent of bonded radioligand (seeing above) before under the displacement of its specific binding site under the test compounds concentration of the present invention of 10 μ mol/l, and be shown in Table 1.

Table 1:

Embodiment	The glycine binding site point of nmda receptor channel
Embodiment	The glycine binding site point of nmda receptor channel		????K _i(μmol/l)	Displacement (%, 10 μ mol/l)
????1	????0.053	100	????K _i(μmol/l)	Displacement (%, 10 μ mol/l)

Embodiment 72

Formolite test, rat

The test of measuring the anti-nociception effect of formula I compound of the present invention is with male rat (Sprague-Dawley, 150-170g) formolite test of carrying out.In formolite test, remarkable different (Pain 4 for D.Dubuisson, S.G.Dennis, 161-174 (1977)) are arranged between first period (in early days) (injection formaldehyde after 0-15 minute) and second period (later stage) (injecting formaldehyde after 15-60 minute).As the direct reaction of PARA FORMALDEHYDE PRILLS(91,95) injection be considered as the acute pain model in early days, and the later stage is considered as continuing (chronic) pain model (T.J.Coderre, J.Katz, A.L.Vaccarino, R.Melzack, Pain, Vol.52, p.259,1993).Interim mensuration The compounds of this invention when second of formolite test is to obtain the information about the effect of compound in chronic/inflammatory pain.

In the experimental animal that can freely obtain, by with formaldehyde (50 μ l, 5%) single subcutaneous injection is induced the nociception reaction in the dorsal part of rear solid end, according to one of them following behavior parameter with this reaction classification: lift and lift injected claw (1 minute), shake and twitch (2 minutes), lick and sting (3 minutes).Inject caused different behavior by writing down formaldehyde, and give the variable of weighting in evaluation the later stage of formolite test observation animal.Wherein the animal normal behaviour of placing the phase even load on whole 4 claws is designated as 0 fen.Be chosen in the function (peritoneal injection: 15 minute of injection formaldehyde administration time before as the The compounds of this invention administering mode; Intravenous injection: 5 minutes).Injected and have in formolite test after the active compound of anti-nociception, the described behavior of animal (1-3 branch) alleviates or even has disappeared.Compare with the control animal of before injection formaldehyde, having accepted carrier (solvent).The nociception behavior is calculated as " pain ratio " (PR).Each behavior parameter is carried out different weights (factor 0,1,2,3).Calculate at interval according to the son of following formula with 3 minutes:

PR＝[(T ₀×0)+(T ₁×1)+(T ₂×2)+(T ₃×3)]/180，

T wherein ₀, T ₁, T ₂And T ₃Be equivalent to the time length (second) that animal shows behavior 0,1,2 or 3 respectively.Compound and vehicle group all comprise n=10 animal.According to the PR value of being calculated, determine the effect of compound, to represent with respect to the change per-cent of contrast.Calculate ED by regression analysis ₅₀For the nociception of formaldehyde inducement, during all showing, all The compounds of this invention wait until strong restraining effect.

Following table has been summed up the result of selected test in the rat formolite test.

Table 2:

Compound	Administering mode	????ED ₅₀
Compound	Administering mode	????ED ₅₀	????1	????i.v.	????7.27mg/kg

Embodiment 73: the parenteral administration formulation

38.5g compound 1 is dissolved in 1 liter of water for injection in room temperature, the condition of oozing such as is adjusted to by adding the injection dextrose anhydrous then.

Claims

General formula I replace 5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-carboxylic acid derivative

Described compound is the form of its preparation, or the form of its acid or alkali, or the form of its salt form, particularly physiological acceptable salt, or the form of its solvate, particularly hydrate; The form of its physiological acceptable salt that forms with positively charged ion or alkali or with negatively charged ion or acid particularly; Can choose wantonly and be its racemic modification form, the steric isomer that it is pure, particularly enantiomorph or diastereomer form, or steric isomer, particularly enantiomorph or diastereomer are with the form of mixtures of any required mixed ratio;

Wherein

R ¹, R ², R ³And R ⁴Be independently from each other

H, F, Cl, Br, I, CN, NO ₂C ₁-C ₁₈-alkyl, C ₂-C ₁₈-alkenyl or C ₂-C ₁₈-alkynyl, described group are respectively side chains or unbranched, and single replacement is polysubstituted or unsubstituted; C ₃-C ₈-cycloalkyl, described group are saturated or undersaturated, single replace polysubstituted or unsubstituted, or wherein at least one ring carbon atom by N, S or the corresponding heterocycle of O alternate; Alkylaryl or miscellaneous alkyl aryl, described group are respectively that single replacement is polysubstituted or unsubstituted; Aryl or heteroaryl, described group are respectively that single replacement is polysubstituted or unsubstituted;

OR ¹¹, OC (O) R ¹¹, C (O) R ¹¹, C (O) OR ¹¹, C (O) NR ¹¹R ^{11 '}, NR ¹¹R ^{11 '}, S (O ₂) R ¹¹Or SR ¹¹, R wherein ¹¹And R ^{11 '}Be independently from each other

H; C ₁-C ₁₈-alkyl, C ₂-C ₁₈-alkenyl or C ₂-C ₁₈-alkynyl, described group are respectively side chains or unbranched, and single replacement is polysubstituted or unsubstituted; C ₃-C ₈-cycloalkyl, described group are saturated or undersaturated, single replace polysubstituted or unsubstituted, or wherein at least one ring carbon atom by N, S or the corresponding heterocycle of O alternate; Alkylaryl or miscellaneous alkyl aryl, described group are respectively that single replacement is polysubstituted or unsubstituted; Aryl or heteroaryl, described group are respectively that single replacement is polysubstituted or unsubstituted;

R ⁵Be selected from

H; C ₁-C ₁₈-alkyl, C ₂-C ₁₈-alkenyl or C ₂-C ₁₈-alkynyl, described group are respectively side chains or unbranched, and single replacement is polysubstituted or unsubstituted; C ₃-C ₈-cycloalkyl, described group are saturated or undersaturated, single replace polysubstituted or unsubstituted, or wherein at least one ring carbon atom by N, S or the corresponding heterocycle of O alternate; Alkylaryl or miscellaneous alkyl aryl, described group are respectively that single replacement is polysubstituted or unsubstituted; Aryl or heteroaryl, described group are respectively that single replacement is polysubstituted or unsubstituted;

R ⁶Be selected from

R ¹²Or ZR ¹², Z=C wherein ₁-C ₆-alkyl, C ₂-C ₆-alkenyl or C ₂-C ₆-alkynyl, described group are respectively side chains or unbranched, and single replacement is polysubstituted or unsubstituted, wherein R ¹²Be selected from

H; C ₁-C ₁₂-alkyl, C ₂-C ₁₂-alkenyl or C ₂-C ₁₂-alkynyl, described group are respectively side chains or unbranched, and single replacement is polysubstituted or unsubstituted; C ₃-C ₈-cycloalkyl, described group are saturated or undersaturated, single replace polysubstituted or unsubstituted, or wherein at least one ring carbon atom by S, O or the corresponding heterocycle of N alternate; Aryl or heteroaryl, described group are respectively that single replacement is polysubstituted or unsubstituted;

C (O) R ¹³, C (O) OR ¹³, C (S) R ¹³, C (S) OR ¹³Or S (O ₂) R ¹³, R wherein ¹³Be selected from

H; C ₁-C ₁₀-alkyl, C ₂-C ₁₀-alkenyl or C ₂-C ₁₀-alkynyl, described group are respectively side chains or unbranched, and single replacement is polysubstituted or unsubstituted; C ₃-C ₈-cycloalkyl, described group are saturated or undersaturated, single replace polysubstituted or unsubstituted, or wherein at least one ring carbon atom by S, O or the corresponding heterocycle of N alternate; Alkylaryl or miscellaneous alkyl aryl, described group are respectively that single replacement is polysubstituted or unsubstituted; Aryl or heteroaryl, described group are respectively that single replacement is polysubstituted or unsubstituted, particularly styroyl, 1-adamantyl, 2-adamantyl, 1-naphthyl or 2-naphthyl, 2-, 3-or 4-pyridyl; Thiazolyl;

SR ¹⁴, R wherein ¹⁴Be selected from

Aryl or heteroaryl, described group are respectively that single replacement is polysubstituted or unsubstituted,

C (O) NR ¹⁵R ¹⁶, C (O) NR ¹⁵NR ¹⁶R ¹⁷, C (NR ¹⁵) NR ¹⁶R ¹⁷, C (S) NR ¹⁵R ¹⁶Or C (S) NR ¹⁵NR ¹⁶R ¹⁷, R wherein ¹⁵, R ¹⁶And R ¹⁷Be independently from each other

H; C ₁-C ₁₈-alkyl, C ₂-C ₁₈-alkenyl or C ₂-C ₁₈-alkynyl, described group are respectively side chains or unbranched, and single replacement is polysubstituted or unsubstituted; C ₃-C ₈-cycloalkyl, described group are saturated or undersaturated, single replace polysubstituted or unsubstituted, or wherein at least one ring carbon atom by S, O or the corresponding heterocycle of N alternate; Alkylaryl or miscellaneous alkyl aryl, described group are respectively that single replacement is polysubstituted or unsubstituted; Aryl or heteroaryl, described group are respectively that single replacement is polysubstituted or unsubstituted;

R ⁷, R ⁸, R ⁹And R ¹⁰Be independently from each other

H, F, Cl, Br, I, CN, NO ₂C ₁-C ₁₀-alkyl, C ₂-C ₁₀-alkenyl or C ₂-C ₁₀-alkynyl, described group are respectively side chains or unbranched, and single replacement is polysubstituted or unsubstituted;

OR ¹⁸, OC (O) R ¹⁸, OC (S) R ¹⁸, C (O) R ¹⁸, C (O) OR ¹⁸, C (S) R ¹⁸, C (S) OR ¹⁸, SR ¹⁸, S (O) R ¹⁸Or S (O ₂) R ¹⁸, R wherein ¹⁸Be selected from

H; C ₁-C ₁₀-alkyl, C ₂-C ₁₀-alkenyl or C ₂-C ₁₀-alkynyl, described group are respectively side chains or unbranched, and single replacement is polysubstituted or unsubstituted; C ₃-C ₈-cycloalkyl, described group are saturated or undersaturated, single replace polysubstituted or unsubstituted, or wherein at least one ring carbon atom by S, O or the corresponding heterocycle of N alternate; Alkylaryl or miscellaneous alkyl aryl, described group are respectively that single replacement is polysubstituted or unsubstituted; Aryl or heteroaryl, described group are respectively that single replacement is polysubstituted or unsubstituted;

NR ¹⁹R ²⁰, NR ¹⁹C (O) R ²⁰, C (NR ¹⁹) NR ²⁰R ²¹, NR ¹⁹C (S) R ²⁰, C (S) NR ¹⁹R ²⁰Or C (S) NR ¹⁹NR ²⁰R ²¹Or S (O ₂) NR ¹⁹R ²⁰, R wherein ¹⁹, R ²⁰And R ²¹Be independently from each other

H, O; C ₁-C ₁₈-alkyl, C ₂-C ₁₈-alkenyl or C ₂-C ₁₈-alkynyl, described group are respectively side chains or unbranched, and single replacement is polysubstituted or unsubstituted; C ₃-C ₈-cycloalkyl, described group are saturated or undersaturated, single replace polysubstituted or unsubstituted, or wherein at least one ring carbon atom by S, O or the corresponding heterocycle of N alternate; Alkylaryl or miscellaneous alkyl aryl, described group are respectively that single replacement is polysubstituted or unsubstituted; Aryl or heteroaryl, described group are respectively that single replacement is polysubstituted or unsubstituted;

Perhaps

R ¹⁹With R ²⁰Or R ²⁰With R ²¹Form C together ₃-C ₈-cycloalkyl, described group are saturated or undersaturated, single replace polysubstituted or unsubstituted, or wherein at least one ring carbon atom by S, O or the corresponding heterocycle of N alternate; Perhaps

R ⁷With R ⁸, R ⁸With R ⁹Or R ⁹With R ¹⁰Together

Formation=CR ²²-CH=CH-CH=or=CH-CR ²²=CH-CH=, wherein R ²²Be selected from

H, F, Cl, Br, I, OH or C ₁-C ₁₀-alkyl, C ₂-C ₁₀-alkenyl or C ₂-C ₁₀-alkynyl, described group are respectively side chains or unbranched, and single replacement is polysubstituted or unsubstituted.
2. 5,6 of the replacement of claim 1,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-carboxylic acid derivative is characterized in that R ⁶Be selected from

H; C ₁-C ₁₀-alkyl, described group do not replace or single replacement or polysubstituted; Phenyl, described phenyl do not replace or single replacement or polysubstituted; Preferred H, CH ₃Or C ₂H ₅, H particularly.
3. 5,6 of claim 1 or one of 2 replacement, 6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-carboxylic acid derivative is characterized in that R ⁵Be selected from

H; C ₁-C ₄-alkyl, described group are side chains or unbranched, and single replacement is polysubstituted or unsubstituted; Phenyl, benzyl or styroyl, described group are that single replacement is polysubstituted or unsubstituted, preferred H, CH ₃Or C ₂H ₅, H particularly.
Claim 1-3 each replacement 5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-carboxylic acid derivative is characterized in that R ⁷, R ⁸, R ⁹And R ¹⁰Be independently from each other

H, F, Cl, Br, I, CN, NO ₂C ₁-C ₆-alkyl, C ₂-C ₆-alkenyl or C ₂-C ₆-alkynyl, described group are respectively side chains or unbranched, and single replacement is polysubstituted or unsubstituted;

OR ¹⁸, C (O) R ¹⁸, C (O) OR ¹⁸Or SR ¹⁸, R wherein ¹⁸Be selected from

H; C ₁-C ₄-alkyl, described group are side chains or unbranched, and single replacement is polysubstituted or unsubstituted; Aryl, described group are that single replacement is polysubstituted or unsubstituted,

Preferably, R ⁷, R ⁸, R ⁹And R ¹⁰Be independently from each other

H, F, Cl, Br, I, CN; C ₁-C ₄-alkyl, described group are side chains or unbranched, and single replacement is polysubstituted or unsubstituted;

OR ¹⁸Or SR ¹⁸, R wherein ¹⁸Be selected from

H, C ₁-C ₄-alkyl, described group are side chains or unbranched, and single replacement is polysubstituted or unsubstituted; Phenyl, described phenyl are that single replacement is polysubstituted or unsubstituted,

Particularly, R ⁷, R ⁸, R ⁹And R ¹⁰Be independently from each other

H, F, Cl, Br, I, CN; CF ₃, CF ₃, the tertiary butyl, isobutyl-, OH ,-OCH ₃,-OCF ₃,-SCH ₃,-O-phenyl.
Claim 1-4 each replacement 5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-carboxylic acid derivative is characterized in that,

R ⁷, R ⁸And R ¹⁰Be H, and R ⁹Be Cl, perhaps

R ⁷And R ⁹Be H, and R ⁸And R ¹⁰Be Cl,

Preferably, R ⁷And R ⁹Be H, and R ⁸And R ¹⁰Be Cl.
Claim 1-5 each replacement 5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-carboxylic acid derivative is characterized in that,

R ⁵＝H，

R ⁶＝H，

R ⁷＝H，

R ⁸＝Cl，

R ⁹=H, and

R ¹⁰＝Cl。
Claim 1-6 each replacement 5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-carboxylic acid derivative is characterized in that R ¹, R ², R ³Or R ⁴Be independently from each other

H, F, Cl, Br, I, CN, NO ₂C ₁-C ₆-alkyl, C ₂-C ₆-alkenyl or C ₂-C ₆-alkynyl, described group are respectively side chains or unbranched, and single replacement is polysubstituted or unsubstituted;

OR ¹¹, OC (O) R ¹¹, C (O) R ¹¹, C (O) OR ¹¹, C (O) NR ¹¹R ^{11 '}, NR ¹¹R ^{11 '}, S (O ₂) R ¹¹Or SR ¹¹, R wherein ¹¹And R ^{11 '}Be independently from each other

H; C ₁-C ₆-alkyl, C ₂-C ₆-alkenyl or C ₂-C ₆-alkynyl, described group are respectively side chains or unbranched, and single replacement is polysubstituted or unsubstituted;

Preferably

H, F, Cl, Br, I, CN, NH ₂, NO ₂C ₁-C ₄-alkyl, C ₂-C ₄-alkenyl or C ₂-C ₄-alkynyl, described group are respectively side chains or unbranched, and single replacement is polysubstituted or unsubstituted;

OR ¹¹, C (O) OR ¹¹Or SR ¹¹, R wherein ¹¹Be selected from

H; C ₁-C ₄-alkyl, C ₂-C ₄-alkenyl or C ₂-C ₄-alkynyl, described group are respectively side chains or unbranched, and single replacement is polysubstituted or unsubstituted;

Particularly

H, F, Cl, Br, I, CN, NH ₂C ₁-C ₄-alkyl, described group are side chains or unbranched, and single replacement is polysubstituted or unsubstituted; SH; OR ¹¹Or C (O) OR ¹¹, R wherein ¹¹Be selected from

H; C ₁-C ₄-alkyl, described group are side chains or unbranched, and single replacement is polysubstituted or unsubstituted;

Or it is preferred especially

H, F, Cl, Br, I, CN, NH ₂, CH ₃, C ₂H ₅, n-propyl, sec.-propyl, isobutyl-, sec-butyl, normal-butyl, the tertiary butyl, CF ₃, CHF ₂, SH, OH, OCH ₃, OC ₂H ₅, C (O) OH, C (O) OCH ₃Or C (O) OC ₂H ₅
Claim 1-7 each replacement 5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-carboxylic acid derivative is characterized in that described compound comprises following compounds or its salt:

-1,3-two chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid,

-1,3-two chloro-10-methoxyl groups-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid,

-1,3-two chloro-8-methyl-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid,

-1,3-two chloro-8-ethyls-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid,

-1,3-two chloro-8-ethyls-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid,

-1,3-two chloro-8-fluoro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid,

-1,3,8-three chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid,

-8-bromo-1,3-two chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid,

-8-iodo-1,3-two chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid,

-1,3-two chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6, the 8-dioctyl phthalate,

-1,3-two chloro-10-methyl-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid,

-1,3-two chloro-10-fluoro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid,

-1,3,10-three chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid,

-10-bromo-1,3-two chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid,

-10-iodo-1,3-two chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid,

-1,3-two chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6, the 10-dioctyl phthalate or

-1,3-two chloro-10-cyano group-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid,

Preferred 1,3-two chloro-5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-formic acid.
Claim 1-8 each replacement 5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-carboxylic acid derivative is characterized in that described compound is its an alkali metal salt, the form of preferred sylvite or sodium salt perhaps is its inorganic acid salt, the form of preferably salt hydrochlorate.
10. prepare wherein R ⁶5,6 of the replacement of the claim 1 of=H, 6a, the method for 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-carboxylic acid derivative is characterized in that, wherein R ⁷, R ⁸, R ⁹And R ¹⁰Have implication described in a kind of claim 1 respectively independently of one another or be provided to the formula II amino benzenes compounds of protecting group

React in 0 ℃-100 ℃ in the presence of trifluoroacetic acid with formula III glyoxylic ester or oxoethanoic acid and formula IV cumarone, wherein R ¹, R ², R ³, R ⁴And R ⁵Have implication described in a kind of claim 1 respectively independently of one another or be provided to protecting group.
11. the method for claim 10 is characterized in that, is 0.25-12 hour between the reaction period, preferred maximum 2 hours, reaction preferably under 20-40 ℃ of temperature, was carried out under the preferred room temperature, and/or reaction is single container reaction.
12. prepare wherein R ⁶5,6 of the replacement of the claim 1 of ≠ H, 6a, the method for 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-carboxylic acid derivative is characterized in that, in case finish reaction according to claim 10, promptly by wherein making R ⁶Hydrogen by R in the claim 1 ⁶Other implication shown in the mode that replaces of group with currently known methods R wherein ⁶The reaction product of=H is reacted in subsequent reaction.
13. each method of claim 10-12 is characterized in that, in the used starting compound of this method, gives residue R ¹, R ², R ³, R ⁴, R ⁵, R ⁷, R ⁸, R ⁹Or R ¹⁰At least one central group provides protecting group, preferably has an OH group at least by OSi (Ph) ₂The tertiary butyl replaces, and has at least a SH group by S-methoxy-benzyl to be replaced, and/or at least one NH ₂Group is by NO ₂Group replaces, and before the purifying end product, in tetrahydrofuran (THF) with tetrabutylammonium with at least one, preferred all OSi (Ph) ₂The tertiary butyl is removed, and/or with the metal amino thing, preferred sodium amide is with at least one, and preferably all are removed methoxy-benzyl, and/or with at least one, preferably all NO ₂Group is reduced into NH ₂
14. each method of claim 10-13 is characterized in that, before the purifying end product, in methyl alcohol or ethanol with KOH solution or NaOH solution in 0 ℃-100 ℃, will have at least one C (O) OCH under preferred 40 ℃ of-60 ℃ of temperature ₃And/or C (S) OCH ₃The product of the method for group or R wherein ⁵=C _1-4The product of the method for alkyl, particularly R wherein ⁵=CH ₃Or C ₂H ₅The product saponification of method.
15. pharmaceutical preparation, wherein contain as at least a claim 1-9 of active ingredient each replacement 5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-carboxylic acid derivative, described compound is the form of its preparation, or the form of its acid or alkali, or the form of its salt, particularly physiological acceptable salt, or the form of its solvate, particularly hydrate; The form of its physiological acceptable salt that forms with positively charged ion or alkali or with negatively charged ion or acid particularly; Can choose wantonly and be its racemic modification form, the steric isomer that it is pure, particularly enantiomorph or diastereomer form, or steric isomer, particularly enantiomorph or diastereomer are with the form of mixtures of any required mixed ratio; And optional suitable additive and/or auxiliary and/or the optional other active ingredient of containing of described pharmaceutical preparation.
16. at least a claim 1-9 each replacement 5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-carboxylic acid derivative is used for the treatment of pain in preparation, particularly neuropathic pain and/or chronic pain, and/or being used for the treatment of application in the migrainous pharmaceutical preparation, wherein said compound is the form of its preparation, or the form of its acid or alkali, or its salt, the particularly form of physiological acceptable salt, or the form of its solvate, particularly hydrate; The form of its physiological acceptable salt that forms with positively charged ion or alkali or with negatively charged ion or acid particularly; Can choose wantonly and be its racemic modification form, the steric isomer that it is pure, particularly enantiomorph or diastereomer form, or steric isomer, particularly enantiomorph or diastereomer are with the form of mixtures of any required mixed ratio.
17. at least a claim 1-9 each replacement 5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-carboxylic acid derivative is used for the treatment of application in the pharmaceutical preparation of the urinary incontinence, itch, tinnitus and/or diarrhoea in preparation, and wherein said compound is the form of its preparation, or the form of its acid or alkali, or its salt, the particularly form of physiological acceptable salt, or the form of its solvate, particularly hydrate; The form of its physiological acceptable salt that forms with positively charged ion or alkali or with negatively charged ion or acid particularly; Can choose wantonly and be its racemic modification form, the steric isomer that it is pure, particularly enantiomorph or diastereomer form, or steric isomer, particularly enantiomorph or diastereomer are with the form of mixtures of any required mixed ratio.
18. at least a claim 1-9 each replacement 5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-carboxylic acid derivative is used for the treatment of/prevents the application in the pharmaceutical preparation of following disease in preparation: epilepsy, Parkinson's disease, Huntington Chorea, glaucoma, osteoporosis, ear is poisoned, follow the Withrawal symptom of alcohol and/or drug abuse, apoplexy, cerebral ischemia, cerebral infarction, cerebral edema, hypoxemia, anoxia and/or be used for anxiety and/or anesthesia, wherein said compound is the form of its preparation, or the form of its acid or alkali, or its salt, the form of physiological acceptable salt particularly, or the form of its solvate, particularly hydrate; The form of its physiological acceptable salt that forms with positively charged ion or alkali or with negatively charged ion or acid particularly; Can choose wantonly and be its racemic modification form, the steric isomer that it is pure, particularly enantiomorph or diastereomer form, or steric isomer, particularly enantiomorph or diastereomer are with the form of mixtures of any required mixed ratio.
19. at least a claim 1-9 each replacement 5,6,6a, 11b-tetrahydrochysene-7-oxa--5-azepine-benzo [c] fluorenes-6-carboxylic acid derivative is used for the treatment of/prevents the application in the pharmaceutical preparation of following illness in preparation: schizophrenia, Alzheimer, increase the psychosis that causes owing to amino acid levels, the AIDS dementia, encephalomyelitis, Tourette ' s syndrome, suffocate term, inflammatory and transformation reactions, dysthymia disorders, medicine and/or alcohol abuse, gastritis, diabetes, cardiovascular diseases, respiratory disease, cough and/or psychosis, wherein said compound is the form of its preparation, or the form of its acid or alkali, or its salt, the form of physiological acceptable salt particularly, or the form of its solvate, particularly hydrate; The form of its physiological acceptable salt that forms with positively charged ion or alkali or with negatively charged ion or acid particularly; Can choose wantonly and be its racemic modification form, the steric isomer that it is pure, particularly enantiomorph or diastereomer form, or steric isomer, particularly enantiomorph or diastereomer are with the form of mixtures of any required mixed ratio.